Vascular disease of the limbs caused by organic arterial obstruction (e.g., arteriosclerosis obliterans) generally involves segmental arteriosclerotic narrowing, and the concomitant obstruction of the lumen in arteries supplying the extremities, particularly in peripheral body parts such as the limbs. In the progression of the disease, organic obstruction leads to occlusion of the artery, which in turn leads to an interruption of the vascular supply to a tissue or organ, resulting in ischemia or necrosis. Ross, R. (1986) N. Engl. J. Med. 314:488. PVD becomes clinically manifest usually between the ages of 50 and 70, and is more prevalent in men than in women. The lower limbs are more frequently involved than the upper limbs, and the most commonly affected vessel is the superficial femoral artery. Schadt et al. (1961) JAMA 175:937
Clinical manifestations of PVD include intermittent claudication, pain at rest, and trophic changes in the involved tissue or limb. Coffman, J. D. (1979) Prog. Cardiovasc. Dis. 22:53. A related clinical condition, Leriche's syndrome, involves isolated aortoiliac disease, and generally manifests as intermittent claudication of the lower back, buttocks, and thigh or calf muscles.
In addition, atherosclerotic PVD, involving the distal aortoiliac arteries and trauma to those vessels, are thus a common cause of vascular impotence. Individuals suffering from such vascular impotence generally have diminished or substantially absent femoral pulses, and generally present with Leriche's syndrome, although claudication may be absent in some cases. Furthermore, atherosclerotic macro- and microvascular disease are major factors contributing to erectile dysfunction in from 30 to 50 per cent of diabetic men who develop impotence.
PVD has been treated medically with some success, using agents such as pentoxifylline, which acts by increasing red cell membrane deformability, thereby reducing blood viscosity (Porter et al. (1982) Am. Heart J. 104:66), although other investigators have not found such viscosity-reducing agents to be efficacious (Mashiah et al. (1978) Br. J. Surg. 65:342). Other approaches in the treatment of PVD have employed oral, parenteral or intravenous administration of vasodilators (Hansteen et al. (1974) Acta Med. Scand. Suppl.! 556:3, Coffmann et al. (1972) Ann. Intern. Med. 76:35), L-carnitine (U.S. Pat. No. 4,968,719 to Brevetti), diuretics such as 1,3-di-n-butyl-7-(2-oxypropyl)xanthine (U.S. Pat. No. 4,784,999 to Angersbach et al.), xanthines and xanthine derivatives (U.S. Pat. Nos. 5,321,029 to Maschler et al. and 4,454,138 to Goring), selective inhibitors of cyclic guanosine 3',5'-monophosphate phosphodiesterase ("cGMP PDE") (U.S. Pat. No. 5,272,147 to Bell et al.), and various classes of chromanols, chromenes and chromans having anti-hypertensive activity (U.S. Pat. No. 4,772,603 to Evans). However, each approach has achieved limited success. Accordingly, there remains a need in the art to provide a more effective method of treating PVD, and particularly PVD-associated vascular impotence.
The present invention is directed to a novel method of treating the aforementioned vascular diseases as well as a novel method for treating vascular impotence as may be associated with such diseases. The treatment involves transurethral administration of a vasoactive agent, particularly a vasodilating agent, as will be described in detail herein.
Transurethral administration of pharmacologically active agents has been described. For example, U.S. Pat. No. 4,478,822 to Haslam et al. relates to a controlled release, thermosetting gel formulation for delivering drugs into a body cavity such as the urethra. Also, U.S. Pat. No. 4,610,868 to Fountain et al. describes a biodegradable lipid matrix composition for administering a drug, wherein the composition is stated to be deliverable through the urethra. Basile et al. (1994), "Medical Treatment of Neurogenic Impotence," Sexual Disabilities 12(1):81-94 describes the intraurethral administration of drugs. PCT Publication No. WO91/16021, U.S. Pat. No. 4,801,587 to Voss et al., and U.S. Pat. No. 5,242,391 to Place et al. relate to the treatment of erectile dysfunction by administration of vasoactive agents into the male urethra. While these references mention urethral drug delivery, the potential importance of administering specific drugs in this manner to induce a desired local or systemic effect has only recently been recognized. Further, applicant is unaware of any art disclosing the effectiveness of transurethral administration of vasoactive agents in the treatment of PVD or PVD-associated vascular impotence.
Accordingly, the present invention provides for an effective method of treating peripheral vascular disease and PVD-associated vascular impotence, by transurethrally administering a vasoactive agent to an individual in need of such treatment. The invention avoids the limitations encountered with other modes of administration, and furthermore, enables the use of lower drug doses than would typically be required with alternative administration techniques.